YM-60828, a novel factor Xa inhibitor: separation of its antithrombotic effects from its prolongation of bleeding time.
The antithrombotic effects of intravenous infusions of YM-60828 ([N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-nap hthyl)methyl]sulfamoyl]acetic acid dihydrochloride), a novel factor Xa inhibitor, argatroban, heparin and dalteparin in an arterio-venous shunt model were studied in comparison with their effects on template bleeding time. In an arterio-venous shunt model, all agents exerted antithrombotic effects in a dose-dependent manner. ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.0087 mg/kg/h. 0.027 mg/kg/h, 22 IU/kg/h and 11 IU/kg/h, respectively. In bleeding time studies, all agents prolonged bleeding time in a dose-dependent manner. Doses (ED2) of YM-60828, argatroban, heparin and dalteparin, which caused 2-fold prolongation of bleeding time in the saline group, were 3.0 mg/kg/h, 0.25 mg/kg/h, 18 IU/kg/h and 26 IU/kg/h. respectively. The risk-benefit ratio (ED2/ID50) of YM-60828 was much greater than that of the other agents. These data suggest that the antithrombotic effect of YM-60828 is separate from its prolongation of bleeding time and that YM-60828 is much safer than conventional anticoagulant agents.
Sato
K
K
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. satoh_k@yamanouchi.co.jp
Kawasaki
T
T
Taniuchi
Y
Y
Hirayama
F
F
Koshio
H
H
Matsumoto
Y
Y
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000991:Antithrombins / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives; D001760:Bleeding Time; D017985:Dalteparin / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D010875:Pipecolic Acids / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides
D000925:Anticoagulants; D000991:Antithrombins; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009281:Naphthalenes; D010875:Pipecolic Acids; D010880:Piperidines; D013449:Sulfonamides; C111032:YM 60828; D006493:Heparin; D001120:Arginine; C031942:argatroban; D017985:Dalteparin